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PubMed1990

Subsensitivity of beta-adrenoceptor responses in asthmatic patients taking regular low dose inhaled salbutamol.

Tremor (Tr), chronotropic (HR) and metabolic (K, Glu) responses to cumulative doses of inhaled salbutamol (100 micrograms to 4000 micrograms) were compared in an age and sex matched group of 7 normal (N) and asthmatic (A) subjects. Comparison of regression lines between groups showed differences in HR and K. This was also reflected in attenuation of maximum responses in group A, for HR and K. These results show subsensitivity of chronotropic and hypokalaemic responses in patients with asthma, which may reflect tachyphylaxis from the effects of long term inhaled salbutamol therapy.

Administration, Inhalation↗
PubMed1989

Etomidate infusions for the control of refractory status epilepticus.

Etomidate was used in eight patients to control status epilepticus which had been refractory to previous anticonvulsant therapy. Cortical activity was measured using a Cerebral Function Analysing Monitor and etomidate administered to achieve a 5 microV mean amplitude, avoiding burst suppression if possible with obliteration of any paroxysmal increase in amplitude. Neuromuscular blockade facilitated endotracheal intubation and mechanical ventilation, and corticosteroid replacement was provided. Rapid control of seizure activity, with cardiovascular stability, was obtained in all cases. Initially the mean infusion rate of etomidate required to achieve adequate suppression of cortical activity was 25 micrograms kg-1 min-1, but several patients exhibited tachyphylaxis. Weaning from the infusion presented difficulties in four patients due to recurring seizures. Adrenocortical function returned to normal within 96 hrs of stopping the infusion. At six month follow up, two patients had died, and two patients had significant reduction in cerebral function compared with their pre-morbid state.

Adult↗
PubMed1994

Activation of protein kinase C does not cause desensitization in rat and rabbit mandibular acinar cells.

We have examined whether activation of protein kinase C by phorbol esters decreases the responsiveness of rat and rabbit mandibular, and rat lacrimal, acinar cells to muscarinic stimulation. Intracellular free calcium concentration ([Ca2+]i) was measured in isolated single acini and cell clusters by fura-2 microspectrofluorimetry. Accumulation of inositol phosphates was measured in acinar cell suspensions. All three cell types showed very similar changes in [Ca2+]i in response to acetylcholine (ACh), although mobilization of Ca2+ required somewhat higher ACh concentrations in rat lacrimal acinar cells than in mandibular acinar cells. There was no evidence for different dose dependencies of the peak and plateau phases of the [Ca2+]i response. The ACh-evoked [Ca2+]i increase in rabbit mandibular acinar cells exhibited desensitization, since it declined in magnitude when cells were stimulated repeatedly with a maximal dose of agonist. The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) rapidly and irreversibly decreased the ACh-evoked [Ca2+]i signals in rat lacrimal acinar cells and reduced ACh-stimulated inositol phosphate accumulation. This inhibitory effect of TPA was most marked in cells stimulated with low doses of ACh, implying that TPA treatment shifted the ACh dose response curve to higher ACh concentrations. In contrast to the results obtained with lacrimal acinar cells, TPA had no effect on the [Ca2+]i and inositol phosphate responses to ACh in either rat or rabbit mandibular acinar cells. These results suggest that, although ACh-evoked [Ca2+]i signals, and hence presumably the stimulus-response coupling machinery, are very similar between different acinar cell types, acinar cells show marked differences in their sensitivity to phorbol esters. The insensitivity of mandibular acinar cell [Ca2+]i signals to TPA also suggests that the secretory tachyphylaxis observed in perfused rat and rabbit mandibular salivary glands is unlikely to be a consequence of negative feedback mediated by protein kinase C.

Acetylcholine↗
PubMed1991

Repeated treatment with dithranol induces a tolerance reaction in keratinocytes in vitro.

The hyperproliferative human keratinocyte line (HaCaT) was tested for dithranol tolerance (tachyphylaxis) at the cellular level. At day 4 after seeding, keratinocytes were treated with 0.3 or 1.0 microM dithranol. Data were compared with those from experiments including additional pretreatments with 0.3 microM at day 3, or at days 1 and 3. Protein content, DNA synthesis and protein synthesis (incorporation of 3H-thymidine and 14C-amino acids per protein) were determined at 24, 48 and 72 h after the last drug exposure. Protein content of attached cells decreased in relation to dose and frequency of treatments. Inhibition of DNA and protein synthesis (38.2% and 32.3%, respectively) also occurred 24 h after a single treatment with 0.3 microM dithranol, but was only 18.4% and 9.1% after pretreatment twice with 0.3 microM dithranol. This tolerance reaction in vitro, after repeated dithranol exposure of human keratinocytes, may be explained by a selective loss of drug-sensitive cells.

Anthralin↗
PubMed1979

Effects of glucocorticosteroids on cultured human skin fibroblasts. III. Transient inhibition of cell proliferation in the early growth stages and reduced susceptibility in later growth stages.

An immediate depression of the rate of cell proliferation occurred upon addition of glucocorticosteroids to cultures of human skin fibroblasts in the early growth stages. A reduced sensitivity or even insensitivity of the fibroblasts to growth inhibition inhibition was found upon the addition of the steroids at later stages of cell growth, when the cell density has increased. The inhibition in the early growth stages is transient and is most pronounced if the cultured medium is not renewed. This transient inhibition is not due to the development of steroid-resistant cell lines, and resembles the effect called tachyphylaxis, as is also observed in vasoconstriction tests.

Betamethasone Valerate↗
PubMed1981

Substance P in the argentaffin carcinoid of the caecum: biochemical and biological characterization.

An argentaffin carcinoid tumour of the caecum which contained serotonin (167 micrograms/g) and consisted predominantly of EC1-cells, was analysed for the presence of peptides using immunohistochemical, biochemical and pharmacological methods. A very high content of 3.9 micrograms/g of immunoreactive substance P was found. The distribution of cells staining positively for substance P matched that of cells containing serotonin. While some immunoreactive somatostatin (3.2 ng/g) was present in the tumour, neurotensin, glucagon, gastrin, and motilin were not found. Part of the substance P immunoreactivity measured most likely represents authentic substance P: it behaved like substance P in two chromatographic systems and in two bioassays, and its activity on the guinea pig ileum was abolished by specific tachyphylaxis towards substance P.

Carcinoid Tumor↗
PubMed1982

Evidence that the contractile response of the guinea-pig ileum to capsaicin is due to substance P release.

The mechanism of action of capsaicin on the guinea-pig isolated ileum was studied. Capsaicin (1.5 x 10(-6) mol 1(-1) produced a large contractile response of the ileum which exhibited marked tachyphylaxis. The response was reduced by treatment of preparations with atropine, 5 x 10(-6) mol 1(-1), and by substance P-autodesensitization, and was abolished by a combination of these treatments. It was concluded that capsaicin released both substance P and acetylcholine from the guinea-pig ileum. Evidence for a cholinergic component in the action of high concentrations of substance P was also obtained and therefore it is proposed that capsaicin releases substance P from neurones in the ileum, and the released substance P in turn stimulates cholinergic neurones to release acetylcholine, as well as producing direct muscle contraction.

Acetylcholine↗
PubMed1980

Development of acute opioid tolerance and dependence in rat striatal neurones.

Striatal neurones in the rat were frequently observed to develop tachyphylaxis to the specific, naloxone-antagonisable depressant effects of methionine- and leucine-enkephalin on spontaneous and L-glutamate-evoked activity. This loss of responsiveness to the enkephalins occurred within a few minutes of the repeated or prolonged application of these peptides and is suggested to reflect a form of acute tolerance. As with chronic opiate tolerance, the acute tolerance of single striatal neurones to the enkephalins appeared to be associated with dependence on these opioids, as evinced by the withdrawal-like hyperactivity that occurred upon terminating the application of the peptides or upon the microelectrophoresis of naloxone.

Animals↗
PubMed1979

Capsaicin-sensitive innervation of the guinea-pig taenia caeci.

1. Stimulation (2--50 Hz) of the mesenteric nerves of the guinea-pig taenia caeci gave rise to contraction of the muscle obtained from animals pretreated with the adrenergic neuron-blocking agent guanethidine. Contraction was the response to stimulation at low frequencies (2--5 Hz) in about half of the untreated preparations as well. 2. The response was abolished by hyocine (4.5 x 10(-7) M), but was unaffected by the ganglionic blocking agent mecamylamine (4.9 x 10(-5) M). Physostigmine (2.4 x 10(-8) M) enhanced the contractions. 3. Capsaicin (9.8 x10(-6) M) elicited a contraction of the taenia caeci followed by a long-lasting tachyphylaxis. Contraction in response to stimulation of the mesenteric nerves was absent after this pretreatment. 4. Neither the response to direct excitation of the cholinergic neural elements of the myenteric plexus, nor the relaxation caused by stimulation of adrenergic fibres were influenced by capsaicin. "Purinergic" relaxation produced by field stimulation (0.5--10 Hz) remained also unchanged. 5. No functional evidence has been found for the presence of parasympathetic preganglionic fibres among the perivascular nerves applying the taenia. 6. It is concluded that capsaicin-sensitive nerves excite cholinergic neurons of the myenteric plexus.

Animals↗
PubMed1983

gamma-Aminobutyric acid and cholinergic transmission in the guinea-pig ileum.

1. The effects of GABA on release of acetylcholine and on contractility of the smooth muscle were studied in the myenteric plexus-longitudinal muscle preparation of the guinea pig. Acetylcholine was determined as radiolabelled transmitter from strips preloaded with 3H-choline. 2. GABA (1 - 300 microM) caused an increase in resting tension of smooth muscle as well as an increase in release of acetylcholine that was considerably reduced by tetrodotoxin. The facilitation by GABA of acetylcholine release exhibited a marked tachyphylaxis. The increase in muscle tension was clearly related to the increase in acetylcholine release. Muscimol (0.1 - 10 microM) also enhanced the release of acetylcholine. The effects of GABA on acetylcholine release and on longitudinal muscle contraction were competitively antagonized by bicuculline and picrotoxin. 3. GABA (1 - 300 microM) inhibited both release of acetylcholine and contractions evoked by electrical stimulation. Muscimol (1, 10 microM) did not modify the evoked release. The inhibitory effects of GABA were not antagonized by bicuculline or picrotoxin. 4. It is suggested that GABA facilitates and inhibits acetylcholine release, and in turn intestinal motility via two receptors with different pharmacological properties.

Acetylcholine↗
PubMed1975

Mode of action of sodium nitroprusside on vascular smooth muscle.

1. Sodium nitroprusside is a potent relaxant of smooth muscles with a predominantly tonic response, e.g. rat aorta contracted by noradrenaline, angiotensin II, Phe2-Lys8-vasopressin, BaC1(2), or KC1, and guinea-pig tracheal smooth muscle contracted by carbachol. 2. Smooth muscle preparations from the splanchnic region and with varying degrees of phasic contractility are less sensitive and develop tachyphylaxis (portal vein, duodenum of the rat) or are unresponsive to sodium nitroprusside (vas deferens, uterus of the rat). 3. Cardiac auricles of the guinea pig are not affected by sodium nitroprusside in either frequency or amplitude or spontaneous contractions. 4. Sdium nitroprusside causes a parallel shift of the dose-response curve of rat aorta to noradrenaline to the right and reduces the maximum response. 5. The drug has no blocking or stimulant effect on alpha- or beta-adrenoceptors, respectively. 6. Sodium nitroprusside inhibits the contractile response of calcium-depleted depolarized rat aorta to extra-cellular calcium. Like verapamil, it inhibits the increment in 45calcium uptake of rabbit aorta elicited by K+. Sodium nitroprusside significantly reduced 45calcium binding by microsomes prepared from rabbit aorta. 7. Rabbit aorta was incubated with lanthanum chloride to prevent calcium influx; sodium nitroprusside reduced the maintained rapid contraction phase in response to noradrenaline which is believed to be based on the intracellular activation of calcium. 8. In rat aorta, cellular cAMP and ATP levels were not found to be affected by the drug. 9. Rabbit aorta, "skinned" by glycerination is unresponsive to sdoium nitroprusside. 10. It is concluded that sodium nitropruside acts on exictation-contraction coupling predominantly in tonic smooth muscle by interfering with both the influx and the intracellular activation of calcium.

Adenosine Triphosphate↗
PubMed1975

Studies on the mechanism of the action of morphine on the peristalsis of guinea pig ileum in situ.

The influence of some drugs on the effect of morphine on the threshold pressure required to elicit peristalsis in the guinea pig ileum in situ was studied, in order to test the hypothesis that this effect of morphine is mediated by catecholamine release. Tachyphylaxis to this effect of morphine was confirmed. Pretreatemnt with two 8 mg/kg doses of reserpine, 24 and 48 hrs before the experiment, significantly reduced the effect of morphine on the pressure threshold. The i.v. administration of 10 mg/kg dl-Dopa re-established the effect of morphine in reserpinized animals to the level of the untreated controls. Pretreatment with guanethidine (15 mg/kg) decreased and even prevented this effect of morphine. Phentolamine pretreatment (10 mg/kg) also significantly inhibited the effect of morphine. Neither DCI nor propranolol influenced this morphine effect. Pretreatment with reserpine, guanethidine or phentolamine reduced the basic pressure threshold needed to elicit peristalsis. The possibility that the decrease of local circulation induced by hypotenison would reduce the local concentration of morphine was rejected because the same doses of guanethidine or phentolamine did not modify the effect of hexamethonium given i.v. in this preparation. All these results support the idea that the effect of morphine on intestinal peristalsis is mediated by a catecholamine acting on alpha-receptors, e.g. norepinephrine.

Animals↗
PubMed1980

Central blood pressure effects of guanylyl-imido-diphosphate and cyclic guanosine-monophosphate.

Injections of guanylyl-imido-diphosphate (250, 500 and 1,000 microgram/kg) into the lateral cerebral ventricle of the anaesthetized cat induced increases in blood pressure and heart rate while the intravenous injections of the same doses were ineffective, thus indicating a central mechanism of action of this compound which activates adenylcyclase at the catalytic subunit. The results support the hypothesis that the activity of cardiovascular centres depends on the prevailing concentration of cAMP. Intracerebroventricular injection of cGMP (125, 250 and 500 microgram/kg) caused hypotension and bradycardia. The effects increased with the dose but were subject to tachyphylaxis. The lack of an effect after intravenous administration indicates a central site of action. This result is in agreement with the Yin Yang hypothesis and suggests that cGMP is a second transmitter in cardiovascular centres which may be involved in central cardiovascular effects in response to stimulation by putative neurotransmitter substances such as acetylcholine.

Animals↗
PubMed1977

Action of some natural peptides on the stomach of the anaesthetized rat.

Different peptides of natural origin were studied for their stimulant activity on the stomach of the anaesthetized rat. The group of the tachykinins (substance P and its analogues) showed a noticeable spasmogenic activity on the whole stomach from the fundus to the pylorus. Threshold doses ranged between 0.1 and 5 microgram/kg by i.v. route and the order of potency was: eledoisin greater than phyllomedusin greater than physalaemin greater than uperolein greater than substance P. A good correlation between the dose and the duration of the spasmogenic effect was always observed and tachyphylaxis never occurred. Experiments carried out with different kinds of inhibitors suggested that tachykinins act directly on the smooth muscle of the stomach. Taking into account also results obtained in other experimental conditions it was possible to state that the N-terminal part of the molecule of these peptides has a certain importance in determining the degree of their potency in the different tests. The peptide motilin, which does not belong to the family from a chemical point of view, was scarcely active, if at all, in modifying the motility of the rat stomach.

Animals↗
PubMed1984

The nature of the stimulatory action of gamma-aminobutyric acid in the isolated perfused dog adrenals.

The effect of gamma-aminobutyric acid (GABA) on catecholamine (CA) release from adrenal medulla was investigated. GABA and GABA agonists, 3-amino-1-propane-sulfonic acid and imidazole-4-acetic acid caused CA release from isolated perfused dog adrenals in a dose-dependent manner, and no tachyphylaxis to GABA was observed. CA release elicited by GABA was antagonized by bicuculline and picrotoxin. This antagonism was specific for GABA- and GABA agonist-induced responses, response to acetylcholine being unaffected. Pretreatment with atropine plus hexamethonium did not affect the response to GABA. GABA-induced CA release was abolished by the removal of Ca2+ from perfusion medium, but not by the removal of Na+ or Cl-. Verapamil, CoCl2 and dibucaine blocked the effect of GABA. A Na+ channel blocker, tetrodotoxin did not reduce GABA-evoked CA release. These results suggest that GABA may interact with its receptor to evoke CA release from adrenal medulla in a fashion of Ca2+-dependence and independence on external Na+ or Cl-.

Acetylcholine↗
PubMed1984

A study of the mode and site of action of capsaicin in guinea-pig heart and rat uterus.

Capsaicin (CAP) has been shown to exert a selective neurotoxic effect on peptidergic primary afferent neurons. The effect of CAP on the isolated guinea-pig left auricle and papillary muscle preparations and on the isolated rat uterus was used to elucidate its mode and site of action with regard to cellular Ca2+ utilization. In the electrically driven left auricle CAP first increased and then decreased the size of the contractions while in the electrically driven papillary muscle CAP caused only a decrease in the contractions. Electrophysiological measurements showed that the initial increase in contraction size coincided with a decrease in the upstroke velocity of the action potential. This membrane-stabilizing effect of CAP seemed also responsible for the decrease in contractile activity. The positive inotropic effect of CAP on the left auricle was concentration-dependent (0.03-6.5 microM). The positive inotropic effect of 0.33 microM CAP was reproducible at intervals of 15 min, whereas tachyphylaxis developed at shorter intervals or higher concentrations of CAP. The percent increase in the size of contractions by 0.33 microM CAP was smaller when [Ca2+]e was doubled but larger when 2.2 microM verapamil or 0.1 mM La3+ was present. The increase in contractions by 0.4-400 microM isoproterenol was greatly reduced by 0.33 microM CAP in a noncompetitive manner. The positive inotropic effect of 2.9 microM glucagon was also inhibited by 0.33 microM CAP. In the isolated anoestrous rat uterus 0.03-3.3 microM CAP caused a transient inhibition of the spontaneous contractions similarly to the effect of 2.2 microM verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Pinacidil, a new vasodilator: pharmacokinetics and pharmacodynamics of a new retarded release tablet in essential hypertension.

In an open study increasing doses of a retarded tablet formulation of pinacidil were given twice daily for four weeks to 9 patients with untreated essential hypertension (WHO I-II). In all patients a decrease in diastolic blood pressure to below 100 mmHg, or a fall exceeding 15 mmHg, was obtained 2 h after tablet intake (p less than 0.02), but in only two patients was the effect maintained after 10 hours (n.s.). At a mean serum concentration of 100 ng/ml 2 h after pinacidil 30 mg, the mean blood pressure had decreased by 14 and 12.7 mmHg in the supine and erect positions, respectively (p less than 0.05). In contrast, mean blood pressure 10 h after the same dose was unchanged, when the mean serum concentration was 47.5 ng/ml. No change in heart rate was observed. Pharmacokinetic and pharmacodynamic investigations showed a tendency towards a more gradual and longer lasting antihypertensive effect and serum concentration-time curve after the retarded tablet than the previous tablet. Pinacidil 40 mg in the retarded tablet reduced mean blood pressure and increased heart rate for at least 8 h. There was a linear correlation between the serum concentration and the change in mean blood pressure, and between the changes in mean blood pressure and in heart rate. There was no indication of tachyphylaxis. A serum level of 50 ng/ml of pinacidil appeared to be the minimal effective concentration. The side effect consisted of fluid retention, and the body weight increased by 1.0 kg (p less than 0.05); four patients complained of oedema.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1977

Modification of experimental UV erythema by external steroids--a reflex photometric study.

A method for reflex photometric detection of the modification of a model of inflammation (UV erythema) by external corticoids is presented. The steroids which most effectively suppress erythema formation are those which have the strongest vasoconstrictor potency also on unchanged skin. A tachyphylaxis phenomenon can also be demonstrated after several applications of a synthetic steroid to the inflammation model.

Adrenal Cortex Hormones↗